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, 14 (4), 388-405

Neuroinflammation in Alzheimer's Disease


Neuroinflammation in Alzheimer's Disease

Michael T Heneka et al. Lancet Neurol.


Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease.


Figure 1
Figure 1. Pathomechanistic sequale of immune activation
Physiological functions of microglia including tissue surveillance and synaptic remodelling are compromized when microglia sense pathological Aβ accumulations. Initially the acute inflammatory response is thought to aid the clearance and to restore tissue homeostasis. Triggering factors and aggravators promote the sustained exposure and immune activation which ultimately leads to chronic neuroinflammation. The perpetuation of microglial activation, persistent exposure to proinflammatory cytokines and process retraction, causes functional and structural changes which finally end in neuronal degeneration.
Figure 2
Figure 2. Micro- and astroglial changes in Alzheimer´s disease brain and APP/PS1 mice
(A) CD11b positive microglia (blue) within a Aβ deposit (brown) in the parietal cortex of a human AD brain section (bar = 50 μm). (B) Activated, Iba1-positive microglia (green) at a Aβ plaque site (red) in a section of a APP/PS1 transgenic mouse (bar = 50 μm). (C) GFAP positive astrocytes (blue) surround the site of Aβ deposition (brown) in the parietal cortex of a human AD brain section (bar = 100 μm). (D) GFAP-positive astrocytes (green) at a Aβ plaque site (red) in a section of a APP/PS1 transgenic mouse (bar = 50 μm). (E) Interleukin-1β positive microglia (brown) in the frontal cortex of a human AD brain section (bar = 25 μm). Courtesy of Drs. Markus Kummer and Michael Heneka.
Figure 3
Figure 3. Amyloidogenic processing of the amyloid precursor protein (APP)
APP is processed by subsequent cleavages of two aspartate-proteases: the β-side cleaving enzyme 1 (BACE1) and the presenilin 1 and 2, which are part of the γ-secretase complex. BACE1 cleavage generates a C-terminal fragment (β-CTF) that is finally processed by presenilin 1 or 2 to liberate the amyloid β peptide, that is prone to aggregate into oligomers.
Figure 4
Figure 4. Impact of amyloid β on microglia
Aβ aggregates (oligomers) act on several TLR receptors on the microglial surface provoking reactions of the innate immune system. On the other side Aβ oligomers are internalized by microglia by the help of the the scavanger receptor A1 (SR-A1), α6β1-integrins, CD36 and CD47.

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